Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) such as collagen and fibronectin in and around damaged tissue, which can lead to permanent scarring, organ malfunction and, ultimately, death. Although we have advanced our understanding of the pathogenesis of kidney fibrosis the translation of these findings to humans has been limited and no proven therapeutic strategies can yet detect or prevent the disease progression. We discovered Secreted Protein Acidic and Rich in Cysteines (SPARC) related modular calcium binding 2 (SMOC2) to be amongst the highest upregulated genes in the kidneys of mice subjected to chronic progressive kidney fibrosis. The mRNA and protein levels of SMOC2 were confirmed to be increased (10 to 60-fold) in three mechanistically distinct mouse models of kidney fibrosis as well as in patients with biopsy-proven kidney fibrosis. In the human fibrotic kidney, SMOC2 was concentrated in epithelial cells of the tubular region while also dispersed around the ?-Smooth Muscle Actin positive myofibroblasts of the interstitial tissue. We show that SMOC2 is critically involved in kidney fibrosis progression because transgenic mice overexpressing SMOC2 exhibit significantly enhanced tubulointerstial kidney fibrosis whereas SMOC2 knockout mice are protected from kidney fibrosis development. Furthermore, our preliminary data suggests that inhibition of SMOC2 in vitro and in vivo using small interfering RNA (siRNA) protects from kidney fibrosis suggesting a critical pathogenic role of SMOC2 in initiation and progression of the disease. In cell culture experiments we found that SMOC2 activates matrix assembly signaling in the fibroblasts to stimulate stress fiber formation, proliferation and migration ? features typical of transitioning into myofibroblasts that are the the effector cells in fibrosis. Whereas, SMOC2 treatment of primary human proximal tubular epithelial cells significantly increases pro fibrotic factors along with an increase in cell size and a decrease in cell number ? features consistent with partial epithelial to mesenchymal transition phenotype. These results have led us to hypothesize that SMOC2 is a key signaling molecule in the pathological secretome of a damaged kidney that plays a critical role in the reparative scaffold; whose continual presence leads to fibrosis. The objective here is to investigate how induction of SMOC2 in fibroblasts and epithelial cells regulate initiation and progression of kidney fibrosis and whether genetic or pharmacologic modulation of SMOC2 is capable of altering the ultimate outcome from kidney fibrosis. Given that there is no information on the functional significance of SMOC2 upregulation following kidney damage the proposed studies aim at uncovering a novel pathway which may provide opportunities for targeted therapies for patients with kidney fibrosis ? an unmet medical need.